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Microcirculation. 2011 Feb;18(2):102-17. doi: 10.1111/j.1549-8719.2010.00071.x.

MEK5 is activated by shear stress, activates ERK5 and induces KLF4 to modulate TNF responses in human dermal microvascular endothelial cells.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520-8089, USA.

Abstract

OBJECTIVE:

ECs lining arteries respond to LSS by suppressing pro-inflammatory changes, in part through the activation of MEK5, ERK5 and induction of KLF4. We examined if this anti-inflammatory pathway operates in human ECs lining microvessels, the principal site of inflammatory responses.

METHODS:

We used immunofluorescence microscopy of human skin to assess ERK5 activation and KLF4 expression in HDMECs in situ. We applied LSS to or overexpressed MEK5/CA in cultured HDMECs and assessed gene expression by microarrays and qRT-PCR and protein expression by Western blotting. We assessed effects of MEK5/CA on TNF responses using qRT-PCR, FACS and measurements of HDMEC monolayer electrical resistance. We used siRNA knockdown to assess the role of ERK5 and KLF4 in these responses.

RESULTS:

ERK5 phosphorylation and KLF4 expression is observed in HDMECs in situ. LSS activates ERK5 and induces KLF4 in cultured HDMECs. MEK5/CA-transduced HDMECs show activated ERK5 and increased KLF4, thrombomodulin, eNOS, and ICAM-1 expression. MEK5 induction of KLF4 is mediated by ERK5. MEK5/CA-transduced HDMECs are less responsive to TNF, an effect partly mediated by KLF4.

CONCLUSIONS:

MEK5 activation by LSS inhibits inflammatory responses in microvascular ECs, in part through ERK5-dependent induction of KLF4.

PMID:
21166929
PMCID:
PMC3075844
DOI:
10.1111/j.1549-8719.2010.00071.x
[Indexed for MEDLINE]
Free PMC Article

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